Psychopathology among offspring of parents with schizophrenia: Relationship to premorbid impairments
Introduction
Schizophrenia is widely held to be a neurodevelopmental disorder (Murray and Lewis, 1987, Weinberger, 1987). The developmental brain abnormalities may originate during the prenatal period and continue through childhood and adolescence. The characteristic symptoms of schizophrenia, which typically emerge in the second or third decade of life, are preceded in many individuals by behavioral and psychological abnormalities dating back to early childhood. It remains unclear whether, and if so, which of these premorbid alterations may predict later emergence of schizophrenia or related psychopathology. Schizophrenia is a heritable disease and many unaffected family members have higher incidence of schizophrenia spectrum disorders and other mental illnesses. Studies of young relatives at high risk (HR), such as offspring of parents with this illness offer a valuable opportunity to characterize premorbid psychopathology in this illness.
Retrospective (Baum and Walker, 1995) and archival-observational studies (Walker et al., 1993) have identified cognitive abnormalities such as attentional and behavioral problems dating back several years before illness onset in schizophrenia. Several high-risk studies, some initiated as early as the early 1960s, have sought to characterize potential premorbid neurobehavioral markers (Cornblatt et al., 1999, Keshavan et al., 2005). These include increased frequency of cognitive and neurological abnormalities (Niemi et al., 2005, Schubert and McNeil, 2004), and premorbid adjustment deficits (Dworkin et al., 1991, Niemi et al., 2005).
Schizotypy, which refers to a set of personality characteristics and experiences related to psychosis, is one of the most frequently described premorbid psychopathological traits in persons with a genetic liability to schizophrenia. Schizotypy is elevated in children at risk for schizophrenia (Carlson and Fish, 2005) and is a sensitive and specific predictor of later development of schizophrenia spectrum disorder (Tyrka et al., 1995). Schizotypy has been found to be associated with attentional impairments in at-risk relatives, (Vollema and Postma, 2002) as well as in adult community volunteers (Bergida and Lenzenweger, 2006). Schizotypy is also associated with cortical gray matter losses in HR relatives (Diwadkar et al., 2006). It is therefore possible that attentional impairments and schizotypy might co-occur in individuals at increased genetic risk for schizophrenia.
A broad range of psychopathological manifestations emerge during adolescence and early adulthood, with a higher frequency of non-specific non-psychotic diagnoses in HR subjects including anxiety and depression (Amminger et al., 2000). In particular, a higher frequency of externalizing, or disruptive behavior disorders (attention deficit hyperactivity disorder, ADHD; conduct disorder, CD and oppositional defiant disorder, ODD) have been described (Keshavan et al., 2003b, Marcus et al., 1993, Rieder and Nichols, 1979, Ross and Compagnon, 2001, Silverton et al., 1988). These disorders have been collectively termed “externalizing” disorders and have been reported to indicate poorer outcome in subjects at risk for schizophrenia in early studies (Garmezy, 1970). Large scale population cohorts suggest that externalizing disorders in childhood may predict an increased prevalence of major psychiatric disorders including schizophrenia later in life (Robins and Price, 1991). Attention deficits have been found to be associated with features of schizophrenia spectrum disorders such as schizotypy (Gooding et al., 2006). For these reasons, it may be argued that externalizing disorders including attention deficit problems characterize a subgroup of HR subjects with a higher propensity to manifest putative premorbid neurobehavioral alterations.
In this study being conducted since 1998, we examined the prevalence of psychopathological diagnoses (Diagnostic and Statistical Manual for Mental disorders; DSM-IV) in a series of HR offspring of parents with schizophrenia. We also examined whether HR subjects with psychopathology have elevations in quantitative indices of premorbid neurobehavioral measures (neurological signs, premorbid maladjustment, and schizotypy). We hypothesized that HR subjects with externalizing psychopathology (HR-EP) would have the most severe alterations, followed (in order of lesser severity) by those with non-externalizing psychopathology (HR-NEP), HR subjects with no psychopathology (HR-N) and healthy comparison (HC) subjects.
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Subjects
Seventy five individuals (34 males and 41 females, mean 15.68 ± 3.27 years range 9.52–21.83) with at least one parent suffering from schizophrenia or schizoaffective disorder were included in this study (high risk offspring; HR). The participants were identified at the Western Psychiatric Institute and Clinic (WPIC), Pittsburgh or related clinical sites. HR subjects were recruited by first approaching patients with schizophrenia with eligible offspring in our outpatient clinical services; we also
Psychopathology in HR subjects
A total of 45 HR individuals out of 75(60%) were diagnosed with one or more DSM-IV axis I psychiatric disorder. Thirty HR subjects had a current axis I disorder and 15 were in remission at the time of entry into the study. Co-morbidity was frequent (18 of 45 HR subjects, 40%). The diagnostic breakup is presented in Table 1.
Comparison of HR subgroups and controls
The HR and HC groups did not differ in age (df = 155; t = .41; P = .68) or gender (Chi2 = .19; P = .67). Highly significant group effects were seen, with HR subjects showing elevations
Discussion
Our findings clearly show that offspring of parents with schizophrenia have an increased frequency of a broad range of axis I psychopathology. A substantial proportion (60%) of genetically at-risk offspring had psychiatric disorders, many of them dating back to childhood, consistent with the neurodevelopmental model of this illness. Of interest is the high prevalence of neurodevelopmental, externalizing disorders as well as mood and anxiety disorders. Recent data from the Edinburgh High Risk
Role of funding source
This work was supported in part by NIMH grants MH 64023, MH 01180 (MSK) a NARSAD Independent Investigator award (MSK), and GCRC grant M01 RR00056. These grants supported all aspects of the study.
Contributors
Dr. Matcheri S. Keshavan designed the study and wrote the protocol. Dr. Rajaprabhaka Rajarethinam and Dr. Debra Montrose managed the literature searches and data analysis. Dr. Vaibhav Diwadkar contributed to consensus diagnostic meetings. All authors contributed to and have approved the final manuscript.
Conflict of interest
There are no conflicts of interest.
Acknowledgement
We are grateful to Diana Merman, MA and Melissa Zeigler, MA for clinical assessments and study coordination.
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